This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
Healthy bone is a mix of 50-70% mineral, 20-40% organic matrix, 5-10% water, and 1-5% lipids and is constantly being recycled into new bone in order to maintain its rigidity and flexibility. (Shea, J. E. et al., Adv. Drug Deliv. Rev. 57 (2005) 945-957; Posner, A. S. and Betts, F, Acc. Chem. Res. 8 (1975) 273-281; Wang, D. et al., Bioconjug. Chem. 18 (2007) 1375-1378). At the beginning of this recycling process, monocytes receive several signals pushing them to differentiate into osteoclasts. Osteoblasts then express Receptor Activator of Nuclear Factor κ B Ligand (RANKL) to the Receptor Activator of Nuclear Factor κ B (RANK) surface receptor in monocytes, initiating the TRAF6 cascade, committing the monocytes to osteoclastogenesis. (Lacey, D. et al., Cell 93 (1998) 165-176; Yasuda, H. et al., Proc. Natl. Acad. Sci. USA 95 (1998) 3597-3602). Mature osteoclasts then initiate healthy catabolic bone resorption. Anabolic processes begin as mesenchymal stem cells (MSCs) are stimulated to become osteoblasts by the BMP-2/Runx2 and Wnt/β-catenin pathways. Matured osteoblasts then deposit osteoid, a component of the bone matrix primarily composed of type I collagen, which mineralizes and becomes new bone. (Vaananen, H. et al., J. Cell Sci. 113 (2000) 377-381; Harada, S., Nature 423 (2003) 349-355).
A narrow balance of catabolism or anabolism is responsible for healthy bone. Alteration of this balance results in diseased bone. Osteoporosis occurs when catabolism surpasses anabolism wherein a two-standard deviation decrease in bone density from healthy bone is observed. In the US, approximately 44 million people have low bone density, and 10 million people suffer from osteoporosis. By 2020, an estimated 61 million are projected to have osteoporosis. (Bartl, R. et al., Osteoporosis: Diagnosis, prevention, therapy, Springer, 2009). In general, osteoporosis can be treated with a regimen of bisphosphonates, which inhibits osteoclasts thereby slowing catabolism as well as healthy bone turnover. This becomes problematic when bone fractures occur and proper bone turnover is retarded by bisphosphonates. These complications include crippling vertebral and hip fractures with estimated costs between in $13.7 billion and $20.3 billion in 2005. (Dempster, D. W., Am J Manag Care. 17 (2011) S164-S169).
Clinical treatment of these fractures generally does not include site-specific anabolic drugs. In fact, the only drugs approved for clinical use on fractures are BMP-2 and BMP-7, which are applied locally for use in open long bone fractures and spinal fusions. (Bishop, G. B. and Einhorn, T. A., Int. Orthop. 31 (2007) 721-727). However, the need for broader application of anabolic drugs to treat bone maladies such as osteoporotic fractures is evident when one considers that 85% of the use of anabolics are off-label. (Ong, K. L. et al., Spine 35 (2010) 1794-1800). Still, the FDA judiciously continues to limit approved use of locally administered drugs to fractures that are already open and at risk of infection.
This limitation necessitates a clinically relevant approach to treating these fractures. Therefore it would be desirable to have a fracture treatment drug that is administered systemically yet targets the fracture site.
A first embodiment of the present disclosure includes a compound for treating bone fractures, comprising: a compound of the formula X-Y-Z, wherein X is a negatively charged oligopeptide; Y is a linker; and Z is an active compound comprising at least one anabolic compound.
A second embodiment of the present disclosure includes the compound the first embodiment, wherein X is an acidic oligopeptide.
A third embodiment of the present disclosure includes the compound of the second embodiment, wherein the acidic oligopeptide comprises not less than 4 and not more than 40, or not less than 4 not less than 30, or not less than 4 and not more than 20 amino acids, or not less than 4 and not more than 15 amino acids, or not less than 4 and not more than 10 amino acids, or less than 4 and not more than 8; the number of amino acids in the oligonucleotide may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 17, 18, 19, 20, or greater.
A fourth embodiment of the present disclosure includes the compound of the third embodiment, wherein the acidic oligopeptide comprises one or more amino acids selected from the group consisting of: D-aspartic acid, L-aspartic acid, D-glutamic acid, and L-glutamic acid.
A fifth embodiment of the present disclosure includes the compound of any one of the first to the forth embodiments, wherein Y is a hydrolysable linker.
A sixth embodiment of the present disclosure includes the compound of any one of the first to the fifth embodiments, wherein Y includes an oxime-ester linkage and/or the molecule 11-aminoundecanoic acid.
A seventh embodiment of the present disclosure includes the compound of any one of the first to the sixth embodiments, wherein Z is at least one anabolic compound comprising a GSK3β inhibitor.
An eighth embodiment of the present disclosure includes the compound of any one of the first to the seventh embodiments, further including at least one spacer, wherein the spacer comprises at least one molecule of 8-amino-2,6-dioxaoctanoic acid.
A ninth embodiment of the present disclosure includes the compound of any one of the first to the eighth embodiments, wherein the anabolic compound is 6′-bromoindirubin-3′-oxime.
A tenth embodiment of the present disclosure includes the compound of any one of the first to the ninth embodiments, wherein the negatively charged oligopeptides comprises D-aspartic acid.
An eleventh embodiment of the present disclosure includes the compound of any one of the first to the tenth embodiments, wherein the compound is:

A twelfth embodiment of the compound of any one of the first to the eleventh embodiments, further comprising at least one group that can simultaneously link to Y to two or more negatively charged oligopeptides.
A thirteenth embodiment of the present disclosure includes the compound of the twelfth embodiment, comprising the following formula:
wherein:X1 and X2 are either branched or linear negatively charged oligopeptides which may or may not be identical; Y is a linker; and W is at least one group comprising at least one amino acid.
A fourteenth embodiment of the present disclosure includes the compound of the thirteenth embodiment, wherein W is at least one lysine.
A fifteenth embodiment of the present disclosure includes the compound of the fourteenth embodiment, wherein the compound is:

A sixteenth embodiment of the present disclosure includes the compound of treating bone fractures, comprising: a compound of the formula X-Y-Z, wherein X is a negatively charged oligopeptide; Y is a linker; and Z is an active compound comprising at least one compound selected from the group consisting of: prostaglandin E1 and prostaglandin E2.
A seventeenth embodiment of the present disclosure includes the compound of the sixteenth embodiment, wherein X is an acidic oligopeptide.
A eighteenth embodiment of the present disclosure includes the compound of the seventeenth embodiment, wherein the acidic oligopeptide comprises not less than 4 and not more than 40, or not less than 4 not less than 30, or not less than 4 and not more than 20 amino acids, or not less than 4 and not more than 15 amino acids, or not less than 4 and not more than 10 amino acids, or less than 4 and not more than 8.
A nineteenth embodiment of the present disclosure includes the compound of the eighteenth embodiment, wherein the acidic oligopeptide comprises one or more amino acids selected from the group consisting of: D-aspartic acid, L-aspartic acid, D-glutamic acid, and L-glutamic acid.
A twentieth embodiment of the present disclosure includes the compound of any one of the sixteenth to the nineteenth embodiments, wherein Y is a hydrolysable linker.
A twenty first embodiment of the present disclosure includes the compound of any one of the sixteenth to the twentieth embodiments, wherein Y is a linker comprising at least one molecule of 11-aminoundecanoic acid.
A twenty second embodiment of the present disclosure includes the compound of any one of the sixteenth to the twenty first embodiments, wherein Z is prostaglandin E1.
A twenty third embodiment of the present disclosure includes the compound of any one of the sixteenth to the twenty second embodiments, further comprising at least one spacer, wherein the spacer comprises at least one molecule of 8-amino-2,6-dioxaoctanoic acid.
A twenty fourth embodiment of the present disclosure includes the compound of any one of the sixteenth to the twenty third embodiments, wherein the negatively charged oligopeptides comprise D-aspartic acid.
A twenty fifth embodiment of the present disclosure includes the compound of any one of the sixteenth to the twenty fourth embodiments, further comprising at least one group that can simultaneously link to Y and two or more negatively charged oligopeptides.
A twenty sixth embodiment of the present disclosure includes the compound of the twenty fifth embodiment, comprising the following formula:
wherein:X1 and X2 are either branched or linear negatively charged oligopeptides which may or may not be identical to one another; Y is a linker; and W is at least one group comprising at least one amino acid.
A twenty seventh embodiment of the present disclosure includes the compound of the twenty sixth embodiment, wherein W is at least one lysine.
A twenty eighth embodiment of the present disclosure includes a method of treating a bone fracture, comprising the steps of: administering a therapeutic amount of any one of the compounds of claims 1-27 to a patient suffering from the bone fracture.
A twenty ninth embodiment of the present disclosure includes the method of the twenty eighth embodiment, further comprising the step of: identifying a patient having a bone fracture.
A thirtieth embodiment of the present disclosure includes a method of treating a bone fracture, comprising the step of: administering to a patient suffering from the bone fracture a therapeutic amount of a compound of the formula,A-B-(MA)n-C-D wherein:A is at least one negatively charged oligopeptide; B is a spacer; C is a linker, wherein the linker includes at least one oligopeptide that is a substrate for the protease cathepsin K;
D is an active compound that promotes the healing of bone fractures comprising at least one compound selected from the group consisting of: prostaglandin E1 and prostaglandin E2; MA is a backbone structure which is linked to both B and C; and n is 1 to 20, or 1 to 100, or 1 to 200, or 1 to 300, or 1 to 400, or 1 to 500, or 1 to 600, or 1 to 700, or 1 to 800, or 1 to 900, or 1 to 1,000, 1 to 1500, 1 to 2000, or any digit greater than or equal to 1 and less than or equal to 2,000; n may 1, 2, 3, 4, 5, 6, 7, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or an digit in the series up to and including 1000.
A thirty first embodiment of the present disclosure includes the method of the thirtieth embodiment, further comprising the step of: identifying a patient having a bone fracture.
A thirty second embodiment of the present disclosure includes the method of any one of the thirtieth to the thirty first embodiments, wherein A is an acidic oligopeptide.
A thirty third embodiment of the present disclosure includes the method of any one of the thirtieth to the thirty third embodiments, wherein the acidic oligopeptide comprises not less than 4 and not more than 40, or not less than 4 not less than 30, or not less than 4 and not more than 20 amino acids, or not less than 4 and not more than 15 amino acids, or not less than 4 and not more than 10 amino acids, or less than 4 and not more than 8.
A thirty fourth embodiment of the present disclosure includes the method of any one of the thirtieth to the thirty third embodiments, wherein the acidic oligopeptide comprises one or more amino acids selected from the group consisting of: D-aspartic acid, L-aspartic acid, D-glutamic acid, and L-glutamic acid.
A thirty fifth embodiment of the present disclosure includes the method of any one of the thirtieth to the thirty fourth embodiments, wherein B is a spacer comprising at least one glycine and at least one 8-amino-2,6-dioxaoctanoic acid.
A thirty sixth embodiment of the present disclosure includes the method of any one of the thirtieth to the thirty fifth embodiments, wherein C comprises at least one glycine.
A thirty seventh embodiment of the present disclosure includes the method of any one of the thirtieth to the thirty sixth embodiments, wherein C is a linker having the formula:-Gly-Gly-Pro-Xle-, wherein:Gly is a glycine; Pro is a proline; and Xle comprises at least one moiety selected from the group consisting of: norleucine, leucine, isoleucine, a hydrophobic amino acid, and an amphipathic amino acid.
A thirty eighth embodiment of the present disclosure includes the method of any one of the thirtieth to the thirty seventh embodiments, wherein D is prostaglandin E1.
A thirty ninth embodiment of the present disclosure includes the method of any one of the thirtieth to the thirty eighth embodiments, wherein MA comprises at least one N-(2-Hydroxypropyl) methacrylamide.
A fortieth embodiment of the present disclosure includes the method of any one of the thirtieth to the thirty ninth embodiments, wherein the compound of the formula A-B-(MA)n-C-D is:

A forty first embodiment of the present disclosure includes the method of any one of the thirtieth to the fortieth embodiments, wherein the compound of the formula: A-B-(MA)n-C-D, further comprises at least one molecule of 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-5-(3-(3-methacrylamidopropyl)thioureido)benzoic acid, wherein the at least one molecule of 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-5-(3-(3-methacrylamidopropyl)thioureido)benzoic acid is linked to MA.
A forty second embodiment of the present disclosure includes the method of any one of the thirtieth to the forty first embodiments, wherein the compound of the formula A-B-(MA)n-C-D further comprises a third group that linked to (MA)n, and/or a fourth group that linked to (MA)n, and/or a fifth group that linked to (MA)n. Some embodiments includes the method of any one of the thirtieth to the forty first embodiments, wherein 1 to 20, or 1 to 100, or 1 to 200, or 1 to 300, or 1 to 400, or 1 to 500, or 1 to 600, or 1 to 700, or 1 to 800, or 1 to 900, or 1 to 1,000, 1 to 1500, 1 to 2000, or any digit greater than or equal to 1 and less than or equal to 2,000 groups, which may or may not be identical to one another, are linked to (MA)n.
A forty third embodiment of the present disclosure includes the method of the forty second embodiment, wherein the compound has the following formula:

A forty fourth embodiment of the present disclosure includes the method of any one of the thirtieth to the forty second embodiments, wherein the negatively charged oligopeptides comprise D-aspartic acid.
A forty fifth embodiment of the present disclosure includes a method of treating a bone fracture, comprising the step of: administering to a patient suffering from the bone fracture a therapeutic amount of a compound of the formula,A-B-(MA)n-C-D, wherein:A is a negatively charged oligopeptide; B is a spacer; C is a linker, wherein the linker includes at least one oligopeptide that is a substrate for the protease cathepsin K; D is an active compound comprising at least one anabolic compound; MA is a backbone structure which is linked to both B and C; and n is 1 to 20, or 1 to 100, or 1 to 200, or 1 to 300, or 1 to 400, or 1 to 500, or 1 to 600, or 1 to 700, or 1 to 800, or 1 to 900, or 1 to 1,000, 1 to 1500, 1 to 2000, or any digit greater than or equal to 1 and less than or equal to 2,000; n may be 1, 2, 3, 4 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or any greater number up to and including 1000.
A forty sixth embodiment of the present disclosure includes the method of the forty fifth embodiment, further comprising the step of: identifying a patient having a bone fracture.
A forty seventh embodiment of the present disclosure includes the method of any one of the forty fifth to the forty sixth embodiments, wherein A is an acidic oligopeptide.
A forty eighth embodiment of the present disclosure includes the method of any one of the forty fifth to the forty seventh, wherein the acidic oligopeptide comprises not less than 4 and not more than 40, or not less than 4 not less than 30, or not less than 4 and not more than 20 amino acids, or not less than 4 and not more than 15 amino acids, or not less than 4 and not more than 10 amino acids, or less than 4 and not more than 8; the number of amino acids in the oligopeptide may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more.
A forty ninth embodiment of the present disclosure includes the method of any one of the forty fifth to the forty eighth embodiments, wherein the acidic oligopeptide comprises one or more amino acids selected from the group consisting of: D-aspartic acid, L-aspartic acid, D-glutamic acid, and L-glutamic acid.
A fiftieth embodiment of the present disclosure includes the method of any one of the forty fifth to the forty ninth embodiments, wherein B is a spacer comprising at least one glycine and at least one 8-amino-2,6-dioxaoctanoic acid.
A fifty first embodiment of the present disclosure includes the method of any one of the forty fifth to the fiftieth embodiments, wherein C comprises at least one glycine.
A fifty second embodiment of the present disclosure includes the method of any one of the forty fifth to the fifty first embodiments, wherein C is a linker having the formula:-Gly-Gly-Pro-Xle-, wherein:Gly is a glycine; Pro is a proline; Xle comprises at least one moiety selected from the group consisting of: norleucine, leucine, isoleucine, a hydrophobic amino acid, and an amphipathic amino acid.
A fifty third embodiment of the present disclosure includes the method of any one of the forty fifth to the fifty second embodiments, wherein D is at least one anabolic compound comprising a GSK3β inhibitor.
A fifty fourth embodiment of the present disclosure includes the method of any one of the forty fifth to the fifty third embodiments, wherein the anabolic compound is 6′-bromoindirubin-3′-oxime.
A fifty fifth embodiment of the present disclosure includes the method of any one of the forty fifth to the fifty fourth embodiments, wherein MA comprises at least one N-(2-Hydroxypropyl) methacrylamide.
A fifty sixth embodiment of the present disclosure includes the method of any one of the forty fifth to the fifty fifth embodiments, wherein the negatively charged oligopeptides comprise D-aspartic acid.
A fifty seventh embodiment of the present disclosure includes a kit for treating a bone fracture comprising: at least one therapeutically effective dose of any of the compound of to any one of the first to the fifty sixth embodiments, or a pharmaceutically acceptable salt thereof.
A fifty eighth embodiment of the present disclosure includes the kit of to the fifty seventh embodiment, wherein said compound in the kit is formulated for injection.
A fifty ninth embodiment of the present disclosure includes the kit of to the fifty eighth embodiment, wherein said compound in the kit is formulated with at least one additional material that helps to preserve the activity of said compound.
A sixtieth embodiment of the present disclosure includes a compound having the formula: Acidic oligopeptide-linker-inhibitor, wherein the acidic oligopeptide comprises from 6 to about 10 aspartic acid units, the linker is a hydrolysable linker comprising (11-aminoundecanoic acid)2 and the inhibitor is a GSK3β inhibitor.
A sixty first embodiment of the present disclosure includes the compound of the sixtieth embodiment, wherein the GSK3β inhibitor is 6′-bromoindirubin.
A sixty second embodiment of the present disclosure includes the compound of the sixtieth embodiment, wherein the compound is:

A sixty third embodiment of the present disclosure includes the compound of sixtieth embodiment, wherein the compound is:

A sixty fourth embodiment of the present disclosure includes a micelle comprising any of the compounds of the sixtieth to the sixty third embodiments.
A sixty fifth embodiment of the present disclosure includes a method of treating a bone fracture comprising administering a therapeutic amount of any of the compounds of the sixtieth to the sixty fourth embodiments.
A sixty fifth embodiment of the present disclosure includes the compound of any of the sixtieth to the sixty fourth embodiments, wherein the aspartic acid units comprise D-aspartic acid.